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Bipolar disorder (BD) features heterogenous clinical presentation and course of illness. It remains unclear how subphenotypes associate with genetic loadings of BD and related psychiatric disorders. We investigated associations between the subphenotypes and polygenic risk scores (PRS) for BD, schizophrenia, and major depressive disorder (MDD) in two BD cohorts from Sweden (N= 5180) and the UK (N= 2577). Participants were assessed through interviews and medical records for inter-episode remission, psychotic features during mood episodes, global assessment of functioning (GAF, function and symptom burden dimensions), and comorbid anxiety disorders. Meta-analyses based on both cohorts showed that inter-episode remission and GAF-function were positively correlated with BD-PRSbut negatively correlated with schizophrenia-PRS (SCZ-PRS)and MDD-PRS. Moreover, BD-PRSwas negatively, and MDD-PRSpositively, associated with the risk of comorbid anxiety disorders. Finally, SCZ-PRSwas positively associated with psychotic symptoms during mood episodes. Assuming a higher PRS of certain psychiatric disorders in cases with a positive family history, we further tested the associations between subphenotypes in index BD people and occurrence of BD, schizophrenia, or MDD in their relatives using Swedish national registries. BD patients with a relative diagnosed with BD had: (1) higher GAF and lower risk of comorbid anxiety than those with a relative diagnosed with schizophrenia or MDD, (2) lower risk of psychotic symptoms than those with a relative diagnosed with schizophrenia. Our findings shed light on the genetic underpinnings of the heterogeneity in clinical manifestations and course of illness in BD, which ultimately provide insights for developing personalized approaches to the diagnosis and treatment.

Objective: Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts. Method: The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort. Results: Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety. Conclusions: The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation. doi: 10.1176/appi.ajp.2010.10040541

Objective: Vulnerability to the triggering of bipolar episodes by childbirth aggregates in families and may define a genetically relevant subtype of bipolar disorder. The authors conducted a search by systematic whole genome linkage scan for loci influencing vulnerability to bipolar affective puerperal psychosis. Method: The authors selected families with bipolar disorder from their previous bipolar disorder genome scan, in which there was at least one family member with a manic or psychotic episode with an onset within 6 weeks of delivery. Individuals were coded as affected if they had been diagnosed with bipolar I disorder; bipolar II disorder; or schizoaffective disorder, bipolar type, according to DSM-IV. A total of 36 pedigrees contributed 54 affected sibling pairs to the cohort. A genome scan with 494 microsatellite markers was analyzed using GENEHUNTER and MAPMAKER/SIBS. Results: A genome-wide significant linkage signal was observed on chromosome 16p13, and a genome-wide suggestive linkage was observed on chromosome 8q24. No significant or suggestive linkage was observed in these regions in our original bipolar scan. Conclusions: This study identifies chromosomal regions that are likely to harbor genes that predispose individuals to bipolar affective puerperal psychosis. The identification of susceptibility genes would enhance understanding of pathogenesis and offer the possibility of improvements in treatment and risk prediction.

Objective: The authors previously reported strong evidence for familial aggregation of postpartum (puerperal) psychotic episodes in women with bipolar disorder. The authors here examine whether vulnerability to postpartum triggering of depressive episodes aggregates in families and assess how this aggregation varies with the definition of postpartum onset. Method: Postpartum depression occurrence was studied in the female members of 120 sibling pairs recruited at a site within an international multicenter study of sibling pairs with recurrent unipolar depression. Employing a range of definitions of postpartum onset, the authors examined concordance for postpartum episode status between sisters. Results: Episodes of depression with onset within 4 weeks of delivery clustered in families, but there was no significant evidence of familial clustering of broadly defined postpartum depression (onset within 6 months). Among women with a family history of narrowly defined postpartum episodes, 42% experienced depression following their first delivery, whereas only 15% of women with no such family history experienced depression following first delivery. The evidence for familiality maximized with a postpartum onset definition of 6-8 weeks. Conclusions: These results implicate familial factors in susceptibility to the triggering of narrowly defined postpartum depressive episodes in women with recurrent major depression. They suggest that a postnatal onset definition of within 6-8 weeks of delivery may be optimal in studies of the triggering of depressive illness by childbirth.

Objective: The authors previously reported two families (pedigrees 324 and 5501) in which Darier's disease--a rare, autosomal dominant skin disease and bipolar disorder cosegregate. In each of these families there is complete cosegregation of mood disorder with a segment of chromosome 12q23-q24, consistent with the existence of a highly penetrant dominant variant. Here molecular genetic analyses aimed at localizing and identifying the susceptibility gene in this region are reported. Method: In the two families, the authors undertook 1) linkage and haplotype studies using 45 highly polymorphic molecular genetic markers in order to delineate the region of interest and 2) direct analysis of genes within this region. Results: Linkage and haplotype information from the most severely affected individuals defined a region of interest that spanned two neighboring regions of 19 megabases (Mb) (D12S362-D12S1646) and 7 Mb(D12S1718-D12S837). Information from all individuals refined the region of interest to 6.5 Mb (D12S127-D12S1646). Systematic study of the coding and flanking intronic regions of 25 known genes within this latter region failed to identify any highly penetrant autosomal dominant disease-conferring mutations in these pedigrees. Conclusions: This linkage and haplotype analysis, together with data from several other linkage studies, provides compelling evidence for the existence in the 12q23-q24 region of one or more genes involved in the pathogenesis of bipolar disorder. Further molecular genetic analysis of this region is required to identify the gene(s).

For more than 150 years, controversy over the status of post-partum psychosis has hindered research and caused considerable confusion for clinicians and women, with potentially negative consequences. We aimed to explore the hypothesis that genetic vulnerability differs between women with first-onset post-partum psychosis and those with bipolar disorder more generally.

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3–2.8, one-sided p= 6.0 × 10−4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p= 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.

Genome‐wide association studies (GWASs) are highly effective at identifying common risk variants for schizophrenia. Rare risk variants are also important contributors to schizophrenia etiology but, with the exception of large copy number variants, are difficult to detect with GWAS. Exome and genome sequencing, which have accelerated the study of rare variants, are expensive so alternative methods are needed to aid detection of rare variants. Here we re‐analyze an Irish schizophrenia GWAS dataset (n= 3,473) by performing identity‐by‐descent (IBD) mapping followed by exome sequencing of individuals identified as sharing risk haplotypes to search for rare risk variants in coding regions. We identified 45 rare haplotypes (>1 cM) that were significantly more common in cases than controls. By exome sequencing 105 haplotype carriers, we investigated these haplotypes for functional coding variants that could be tested for association in independent GWAS samples. We identified one rare missense variant in PCNTbut did not find statistical support for an association with schizophrenia in a replication analysis. However, IBD mapping can prioritize both individual samples and genomic regions for follow‐up analysis but genome rather than exome sequencing may be more effective at detecting risk variants on rare haplotypes.

Major depressive disorder is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome and have reported growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide important routes for identification of disease mechanisms by focusing on a specific process, excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether major depressive disorder polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRSs) and the whole genome, excluding NETRIN1 pathway genes (genomic-PRSs), were associated with white matter microstructure.

Darier disease (DD) is an autosomal dominant skin disorder caused by mutations in ATP2A2encoding the sarco/endoplasmic reticulum Ca2+ATPase Isoform 2 (SERCA2). Evidence of a population‐level association between DD and psychiatric disorders suggests that mutations in ATP2A2may have pleiotropic effects on the brain as well as skin. Evidence of genotype–phenotype relationships between ATP2A2mutations and neuropsychiatric phenotypes would further support this suggestion. We investigated genotype–phenotype correlations between lifetime neuropsychiatric features and ATP2A2mutation type (dichotomized into likely gene disrupting [LGD] or protein altering) in 75 unrelated individuals with DD. We also looked for evidence of clustering of mutations within SERCA2 according to neuropsychiatric features. Combining our data with the existing literature, the rate of LGD mutations was found to be significantly higher among DD cases/families with bipolar disorder, schizophrenia, or affective psychosis (p= .011). We also found a significant relationship between mutations located in the S4–M4 region of the protein and the presence of a severe neuropsychiatric phenotype (p= .032). Our findings add support to the hypothesis that Darier‐causing mutations in ATP2A2confer susceptibility to neuropsychiatric dysfunction, in particular severe psychiatric illness. This, together with evidence from research on common polymorphisms confirms ATP2A2as a gene at which variation influences susceptibility to major psychiatric illness.

Objective: Puerperal psychosis, an episode of mania or psychosis precipitated by childbirth, follows approximately one in 1,000 deliveries. The evidence of clinical, outcome, and genetic studies supports the hypothesis that the majority of puerperal psychotic episodes are manifestations of an affective disorder diathesis with a puerperal trigger. Family studies of puerperal psychosis consistently demonstrate familial aggregation of psychiatric (particularly affective) disorder and suggest a major overlap in the familial factors predisposing to puerperal psychosis and bipolar disorder. The single large study that used direct interview of relatives suggested that familial factors play a role in vulnerability to puerperal triggering itself. The authors' goal was to test this hypothesis further. Method: They conducted a study of the occurrence of episodes of puerperal psychosis in families multiply affected with bipolar disorder participating in an ongoing molecular genetic study of bipolar disorder in sibling pairs. Results: Episodes of puerperal psychosis followed 81 (26%) of 313 deliveries to 152 parous women with bipolar disorder, 58 (38%) of whom had at least one puerperal psychotic episode. Puerperal episodes clustered in families. Episodes of puerperal psychosis occurred in 74% (N=20) of the 27 parous women with bipolar disorder who had a family history of puerperal psychosis in a first-degree relative but in only 30% (N=38) of the 125 women with bipolar disorder with no such family history. Conclusions: These results conclusively demonstrate that familial (probably genetic) factors are implicated in susceptibility to triggering of puerperal episodes in women with bipolar disorder. These findings have implications for future research and will be of use clinically in the management of women with bipolar disorder who are considering pregnancy.

The etiologies of bipolar disorder (BD) and schizophrenia include a large number of common risk alleles, many of which are shared across the disorders. BD is clinically heterogeneous and it has been postulated that the pattern of symptoms is in part determined by the particular risk alleles carried, and in particular, that risk alleles also confer liability to schizophrenia influence psychotic symptoms in those with BD. To investigate links between psychotic symptoms in BD and schizophrenia risk alleles we employed a data‐driven approach in a genotyped and deeply phenotyped sample of subjects with BD. We used sparse canonical correlation analysis (sCCA) (Witten, Tibshirani, & Hastie, [Witten, D. M., 2009]) to analyze 30 psychotic symptoms, assessed with the OPerational CRITeria checklist, and 82 independent genome‐wide significant single nucleotide polymorphisms (SNPs) identified by the Schizophrenia Working group of the Psychiatric Genomics Consortium for which we had data in our BD sample (3,903 subjects). As a secondary analysis, we applied sCCA to larger groups of SNPs, and also to groups of symptoms defined according to a published factor analyses of schizophrenia. sCCA analysis based on individual psychotic symptoms revealed a significant association (p= .033), with the largest weights attributed to a variant on chromosome 3 (rs11411529), chr3:180594593, build 37) and delusions of influence, bizarre behavior and grandiose delusions. sCCA analysis using the same set of SNPs supported association with the same SNP and the group of symptoms defined “factor 3” (p= .012). A significant association was also observed to the “factor 3” phenotype group when we included a greater number of SNPs that were less stringently associated with schizophrenia; although other SNPs contributed to the significant multivariate association result, the greatest weight remained assigned to rs11411529. Our results suggest that the canonical correlation is a useful tool to explore phenotype–genotype relationships. To the best of our knowledge, this is the first study to apply this approach to complex, polygenic psychiatric traits. The sparse canonical correlation approach offers the potential to include a larger number of fine‐grained systematic descriptors, and to include genetic markers associated with other disorders that are genetically correlated with BD.

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype. A genome-wide association meta-analysis of individuals with clinically assessed or self-reported depression identifies 44 independent risk loci. Comparisons with other psychiatric disorders and candidate gene analyses provide new insights into major depressive disorder.

Studies have suggested that Research Diagnostic Criteria for Schizoaffective Disorder Bipolar type (RDC‐SABP) might identify a more genetically homogenous subgroup of bipolar disorder. Aiming to identify loci associated with RDC‐SABP, we have performed a replication study using independent RDC‐SABP cases (n= 144) and controls (n= 6,559), focusing on the 10 loci that reached a p‐value <10−5for RDC‐SABP in the Wellcome Trust Case Control Consortium (WTCCC) bipolar disorder sample. Combining the WTCCC and replication datasets by meta‐analysis (combined RDC‐SABP, n= 423, controls, n= 9,494), we observed genome‐wide significant association at one SNP, rs2352974, located within the intron of the gene TRAIPon chromosome 3p21.31 (p‐value, 4.37 × 10−8). This locus did not reach genome‐wide significance in bipolar disorder or schizophrenia large Psychiatric Genomic Consortium datasets, suggesting that it may represent a relatively specific genetic risk for the bipolar subtype of schizoaffective disorder.

Objective: The purpose of this study was to identify the specific expanded CAG/CTG trinucleotide repeat associated with bipolar disorder. Method: The study employed an efficient multistage approach for using a genomic CAG/CTG screening set. Results: The authors found no evidence of expanded repeats at 43 polymorphic autosomal loci and seven X chromosomal loci. Secondary screening was pursued at the only locus that contained a large allele (37 repeats) in the primary screening. No association was found between allele size and diagnostic status. Conclusions: It is highly unlikely that expansions in repeat size at any of the 50 candidate trinucleotide repeat loci examined are responsible for the association between expanded CAG/ CTG repeats and bipolar disorder. However, although the authors prioritized the repeats that were a priori most likely to be involved, the study does not reject the more general hypothesis that expanded CAG/CTG repeats are implicated in the pathogenesis of bipolar disorder.

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Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10−8). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants (‘SNP heritability’) as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.

By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10−9). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.

Studies of families and twins show the importance of genetic factors affecting susceptibility to bipolar disorder and suggest substantial genetic and phenotypic complexity. Robust and replicable genome-wide significant associations have recently been reported in genome-wide association studies at several common polymorphisms, including variants within the genes CACNA1C, ODZ4, and NCAN. Strong evidence exists for a polygenic contribution to risk (ie, many risk alleles of small effect). A notable finding is the overlap of susceptibility between bipolar disorder and schizophrenia for several individual risk alleles and for the polygenic risk. By contrast, genomic structural variation seems to play a smaller part in bipolar disorder than it does in schizophrenia. Together, these genetic findings suggest directions for future studies to delineate the aetiology and pathogenesis of bipolar disorder, indicate the need to re-evaluate our diagnostic classifications, and might eventually pave the way for major improvements in clinical management.

Recent advances in high-throughput genotyping have made possible genome-wide association studies (GWAS) in which hundreds of thousands of common DNA variants spread across all the chromosomes are examined in a large number of individuals rapidly and for a realistic cost. The GWAS approach has been successfully used to identify common susceptibility variants involved in many non-psychiatric diseases, such as heart disease, diabetes, Crohn's disease, and in normal traits such as height. The typical finding is numerous susceptibility loci, each of which has a small effect size. Genome-wide association studies are similarly providing robust and replicable evidence for genes and, hence, proteins and biological systems/pathways that are involved in the aetiology and pathogenesis of major psychiatric disorders, including schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, autism and Alzheimer's disease. This article outlines for the busy psychiatrist some of the key messages emerging from this line of research.

Genome‐wide studies in major depression have identified few replicated associations, potentially due to heterogeneity within the disorder. Several studies have suggested that age at onset (AAO) can distinguish sub‐types of depression with specific heritable components. This paper investigates the role of AAO in the genetic susceptibility for depression using genome‐wide association data on 2,746 cases and 1,594 screened controls from the RADIANT studies, with replication performed in 1,471 cases and 1,403 controls from two Munich studies. Three methods were used to analyze AAO: First a time‐to‐event analysis with controls censored, secondly comparing controls to case‐subsets defined using AAO cut‐offs, and lastly analyzing AAO as a quantitative trait. In the time‐to‐event analysis three SNPs reached suggestive significance (P< 5E−06), overlapping with the original case–control analysis of this study. In a case–control analysis using AAO thresholds, SNPs in 10 genomic regions showed suggestive association though again none reached genome‐wide significance. Lastly, case‐only analysis of AAO as a quantitative trait resulted in 5 SNPs reaching suggestive significance. Sex specific analysis was performed as a secondary analysis, yielding one SNP reaching genome‐wide significance in early‐onset males. No SNPs achieved significance in the replication study after correction for multiple testing. Analysis of AAO as a quantitative trait did suggest that, across all SNPs, common genetic variants explained a large proportion of the variance (51%, P= 0.04). This study provides the first focussed analysis of the genetic contribution to AAO in depression, and establishes a statistical framework that can be applied to a quantitative trait underlying any disorder. © 2012 Wiley Periodicals, Inc.

This study is the first that formally tests for genetic heterogeneity of bipolar disorder (BD) according to age at onset (AAO) sub‐groups by combining positional cloning and candidate gene approaches. Our previous genome‐wide linkage‐scan identified five genomic regions linked to early‐onset form of BD. The present study uses association analysis to test genetic heterogeneity of candidate genes located in these five regions in a sample of 443 unrelated bipolar patients and 1,731 controls. The study involved the following steps: (1) test of heterogeneity by comparing early‐onset BD patients versus later‐onset BD patients; and (2) for significant results in step 1, comparison of early‐onset BD patients and later‐onset BD patients separately to controls. Two types of analyses were used: the single SNP test and the gene‐based association test. We provide evidence for genetic heterogeneity within the ADRB2 (beta‐2adrenoreceptor) gene region that is specifically associated with the early onset form of BD with an OR of 1.8. Unfortunately, the genotyping coverage of ADRB2 in the Wellcome Trust Case Control Consortium sample meant undermined our efforts to undertake a replication. However, as the ADRB2 gene product directly interacts with the CACNA1C gene product, and is known to be implicated in BD susceptibility, we conclude that further exploration of the relationships between ADRB2 and BD needs to be undertaken. © 2012 Wiley Periodicals, Inc.

The GWAS‐based association of CACNA1Cwith bipolar disorder (BPD) is one of the strongest genetic findings to date. CACNA1Cbelongs to the family of CACNgenes encoding voltage‐dependent calcium channels (VDCCs). VDCCs are involved in brain circuits and cognitive processes implicated in BPD and schizophrenia (SZ). Recently, it was shown that rare copy number variations (CNVs) are found at an increased frequency in SZ and to a lesser extent also in BPD, suggesting the involvement of CNVs in the causation of these diseases. We hypothesize that CNVs in CACNgenes can influence the susceptibility to BPD, SZ, and/or schizoaffective disorder (SZA). A search for CNVs in eight CACNgenes in a patient‐control sample of European decent was performed. A total of 709 BP patients, 645 SZ patients, 189 SZA patients, and 1,470 control individuals were screened using the Multiplex Amplicon Quantification (MAQ) method. We found a rare, partial deletion of 35.7 kb in CACNA2D4in two unrelated late onset bipolar I patients and in one control individual. All three deletions shared the same breakpoints removing exons 17–26 of CACNA2D4, comprising part of the CACHE domain. Based on the data we cannot claim causality to BPD of the identified CACNA2D4deletion but nevertheless this deletion can be important in unraveling the underlying processes leading to psychiatric diseases in general and BPD in particular. © 2012 Wiley Periodicals, Inc.

The author discusses the state of psychiatric research, arguing that the field needs a unified theory for collaborative research such as the Higgs field theory in physics. He notes several advances in the study of human mind and behavior, including neuroeconomics, the molecular genetics of mental illnesses, and computer modeling of brain neuronal circuitry. He advocates for funding of research to consolidate these various methods of psychiatry and brain study.

Psychiatrists make important and specific contributions to the care of those with mental health problems and high-quality services should enable patients to benefit optimally from a psychiatrist’s distinctive skills. In this article we seek to identify and consider the core expertise of the psychiatrist.

Strong evidence of linkage between chromosomal region 6q16q22 and bipolar affective disorder BPAD has previously been reported. We conducted a systematic association mapping of the 6qlinkage interval using 617 SNP markers in a BPAD case–control sample of German descent cases  330, controls  325. In this screening step, 46 SNPs showed nominally significant BPADassociation Pvalues between 0.0007 and 0.0484. Although none of the 46 SNPs survived correction for multiple testing, they were genotyped in a second and ethnically matched BPAD sample cases  328, controls  397. At the melaninconcentratinghormonereceptor2MCHR2 gene, we found nominal association in both the initial and second BPAD samples combined P  0.008. This finding was followed up by the genotyping of 17 additional MCHR2SNPs in the combined sample in order to define our findings more precisely. We found that the MCHR2locus can be divided into three different haplotypeblocks, and observed that the MCHR2association was most pronounced in BPAD male patients with psychotic symptoms. In two neighboring blocks, putative riskhaplotypes were found to be 7 more frequent in patients block II: 23.3 vs. 16.2, P  0.005, block III: 39.2 vs. 32.0, P  0.024, whereas the putative protective haplotypes were found to be 5–8 less frequent in patients block II: 11.6 vs. 16.4, P  0.041, block III: 30.0 vs. 38.8, P  0.007. The corresponding odds ratios singlemarker analysis ranged between 1.25 and 1.46. Our findings may indicate that MCHR2is a putative risk factor for BPAD. These findings should be interpreted with caution and replicated in independent BPAD samples. © 2009 WileyLiss, Inc.

The chromosomal region 12q24 has been previously implicated by linkage studies of both bipolar disorder and unipolar mood disorder and we have reported two pedigrees segregating both bipolar disorder and Dariers disease that show linkage across this region. The gene P2RX7is located in this chromosomal region and has been recently reported as a susceptibility gene for bipolar disorder and unipolar depression. The nonsynonymous SNP rs2230912 resulting in aminoacid polymorphism Q460R showed the strongest association and has been postulated to be pathogenically relevant. We have investigated this gene in a large UK casecontrol sample bipolar I disorder N  687, unipolar recurrent major depression N  1,036, controls N  1,204. Neither rs2230912 nor any of 8 other SNPs genotyped across P2RX7was found to be associated with mood disorder in general, nor specifically with bipolar or unipolar disorder. Further, sequencing of our two chromosome 12linked bipolarDarier families showed no evidence of rare variants at P2RX7that could explain the linkage. Our data do not provide support for rs2230912 or the other polymorphisms studied within the P2RX7 locus, being involved in susceptibility to mood disorders. © 2009 WileyLiss, Inc.

Retinoid receptors (RARs and RXRs) regulate brain morphogenesis and function. Defects in these receptors may contribute to schizophrenia or other psychiatric diseases. To test the hypothesis that genetic variants of the retinoid receptor genes may predispose to schizophrenia and other psychiatric diseases, the six RAR and RXR genes and a heterodimer partner, the NURR1 gene, were scanned in 100 schizophrenia patients, along with pilot studies in 20–24 patients with bipolar disorder (BPD), attention‐deficit hyperactivity disorder (ADHD), autism, or alcoholism. A total of 5.4 megabases of genomic sequence was scanned. No variants affecting protein structure or expression (VAPSEs) were found in four of the genes. One uncommon missense variant was found in each of the RARβ, RARγ, and RXRγ genes. We conclude that structural variants in the RAR/RXR and NURR1 genes do not play a major role in the etiology of schizophrenia. © 2004 Wiley‐Liss, Inc.

Chromosome 12q23‐q24 has been implicated by several linkage studies as harboring a gene for bipolar affective disorder. We performed linkage disequilibrium (LD) mapping with 17 microsatellite markers across a 1.6 Mb‐wide segment forming the central part of our narrowest linkage region. A significant signal (P = 0.0016) was identified for one microsatellite marker in our UK Caucasian case‐control sample (347 cases, 374 controls). Genes, including regulatory elements, around this marker were screened for mutations and the LD structure of the region determined by genotyping 22 SNPs and insertion/deletion polymorphisms in 94 individuals. A set of 11 haplotype tagging (ht) SNPs was genotyped in our sample using a two‐stage procedure. Two SNPs (rs3847953 and rs933399) and an insertion/deletion with putative functional relevance (which are in high LD with each other and with the microsatellite marker) showed significant or nearly significant association with bipolar disorder after Bonferroni‐correction (reaching nominal P values from P = 0.002 to P = 0.005). In a sample of 110 UK Caucasian parent–offspring trios there was a trend for an over transmission in the same direction that failed to meet conventional levels of statistical significance. Our data provide evidence for association between bipolar mood disorder and markers on chromosome 12q23‐q24 but need replication in independent samples. © 2004 Wiley‐Liss, Inc.

Mutations in the gene coding for methyl‐CpG‐binding protein 2 (MECP2) cause Rett syndrome (RTT) and have also been reported in a number of X‐linked mental retardation syndromes. Furthermore, putative mutations recently have been described in a few autistic patients and a boy with language disorder and schizophrenia. In this study, DNA samples from individuals with schizophrenia and other psychiatric diseases were scanned in order to explore whether the phenotypic spectrum of mutations in the MECP2 gene can extend beyond the traditional diagnoses of RTT in females and severe neonatal encephalopathy in males. The coding regions, adjacent splicing junctions, and highly conserved segments of the 3′‐untranslated region (3′‐UTR) were examined in 214 patients, including 106 with schizophrenia, 24 with autism, and 84 patients with other psychiatric diseases by detection of virtually all mutations‐single strand conformation polymorphism (SSCP) (DOVAM‐S). To our knowledge, this is the first analysis of variants in conserved regions of the 3′‐UTR of this gene. A total of 5.2 kb per haploid gene was analyzed (1.5 Mb for 214 patients). A higher frequency of missense and 3′‐UTR variants was found in autism. One missense and two 3′‐UTR variants were found in 24 patients with autism versus one patient with a missense change in 144 ethnically similar individuals without autism (P = 0.009). These mutations suggest that a possible association between MECP2 mutations and autism may warrant further study. © 2004 Wiley‐Liss, Inc.

Sex steroids exert potent effects on mood and mental state in humans. They may contribute to the risk of psychiatric disorders. To investigate this hypothesis, coding and splice junction sequences of the androgen receptor gene were scanned in genomic DNA samples to search for variants affecting protein structure and expression (VAPSEs). Ninety-six schizophrenics, along with pilot samples of patients with bipolar disorder, attention-deficit hyperactivity disorder, alcoholism and autism were analyzed with DOVAM-S, a robotically enhanced, optimized form of single-strand conformation polymorphism analysis. A total of 669 kb of genomic sequence was analyzed. Two VAPSEs were identified R726L was found in one of 17 scanned alcoholics, and P516S, a novel VAPSE, was identified in one of three phobia patients. There were no length trends of the CAG triplets associated with schizophrenia. R726L and P516S occur at highly conserved amino acids. Further study is required to assess whether these VAPSEs contribute to the risk of alcoholism or phobia or other diseases.

Anticipation is the phenomenon whereby a disease becomes more severe and/or presents with earlier onset as it is transmitted down through generations of a family. The only known mechanism for true anticipation is a class of mutations containing repetitive sequences exemplified by the pathogenic trinucleotide repeat. Studies of bipolar disorder (BPD) are consistent with the presence of anticipation and, by inference, the possibility that trinucleotide repeats contribute to this disorder, although it is possible that these data are the result of methodological problems. On the assumption that anticipation in BPD may be real, several surveys of the genome of BPD probands for large trinucleotide repeats have been conducted, as have studies of many repeat-containing candidate genes. No pathogenic triplet repeat has yet been unambiguously implicated. © 2003 Wiley-Liss, Inc.

In the search for chromosome 12 genes potentially involved in the pathogenesis of bipolar disorder we will screen Phenylalanine hydroxylase and human LIMhomeobox LHX5 genes for sequence variants, both of which have been suggested as candidate genes. The genes lie on chromosome 12q23–24, near the Darier's disease gene, ATP2A2. We have previously reported two families in which the pattern of segregation of illness is consistent with genetic linkage between this chromosomal region and a putative highly penetrant autosomal dominant major affective disorder locus pedigree 324, maximum LOD2.1 pedigree 5501, maximum LOD3.6.

Genes involved in estrogen pathways have been proposed as possible candidates influencing susceptibility to bipolar disorder and the affective symptoms suffered by many women during the puerperal period. The estrogen receptor alpha (ERα) gene in particular has been a subject of interest and has recently been intensively screened for variations of potential relevance to psychiatric disorders, resulting in the identification of four mutations in individuals with bipolar disorder or puerperal psychosis. We have examined the frequency of these four ERα variations in a case control study using a group of mixed gender bipolar individuals (N = 231), further classified into subsets of parous bipolar females with (N = 112) and without (N = 50) puerperal psychosis, and a non-psychiatric comparison group (N = 110). We have also investigated the families in which the variations were initially detected, for evidence of co-segregation of the variants with mood disorder. We found no evidence in our case control sample to support the involvement of any of the ERα variations in either the aetiology of bipolar disorder or puerperal triggering of bipolar episodes. Nor did we find co-segregation of ERα variants and disease in any of the four families examined. We conclude that variation in the coding sequence and flanking splice junctions of the ERα gene does not play an important pathogenic role in the majority of cases of Bipolar Disorder or Bipolar Affective Puerperal Psychosis. © 2003 Wiley-Liss, Inc.

Bipolar women have a marked vulnerability to puerperal psychosis, an episode of mania or psychosis following childbirth. We have conducted a family history study to examine the question of whether a vulnerability to puerperal episodes of illness is a marker for a more familial form of bipolar disorder. A consecutive series of 103 bipolar disorder probands were recruited in a lithium clinic and given a semi-structured interview, including a detailed family history. For the 52 female probands, information was also obtained about the relationship of episodes to childbirth. The morbid risk of affective disorder in first-degree relatives of bipolar women who had suffered an episode of mania, hypomania or schizoaffective mania with onset within 6 weeks of childbirth was significantly higher than that in relatives of parous bipolar women with no episodes in relation to childbirth (P0.0077). Despite relatively small numbers, this study provides evidence to support the hypothesis that puerperal episodes identify a more familial subtype of bipolar disorder.

Recent family and twin study findings suggest that ADHD when comorbid with conduct problems may represent a particularly familial and heritable form of ADHD. Although several independent groups have shown association between the DRD4 7 repeat allele and ADHD, others have failed to replicate this finding. Previous TDT analyses of UK and Eire samples had also been negative. We set out to further examine the role of DRD4 but selecting a subgroup of children with ADHD and comorbid conduct problems. Families were recruited from Manchester, Ireland, Birmingham and London clinics. From these, 67 children who fulfilled diagnostic criteria for ADHD and who displayed conduct disorder symptoms were selected. TDT analysis, which had previously yielded negative results for the total sample, showed evidence of association between DRD4 and “ADHD with conduct problems” (7 repeat allele-24 transmissions, 13 non-transmissions; one-tailed P = 0.05). These results provide further support for the role of DRD4 in ADHD. Furthermore, these results when considered together with family and twin study findings, suggest that those children with ADHD and comorbid conduct problems may be particularly informative for molecular genetic studies of ADHD. Further work is needed to examine these phenotype issues. © 2002 Wiley-Liss, Inc.

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable, common psychiatric disorder of childhood that probably involves several genes. There are several lines of evidence suggesting that the nicotinic system may be functionally significant in ADHD. First, nicotine promotes the release of dopamine and has been shown to improve attention in adults with ADHD, smokers, and nonsmokers. Second, ADHD is a significant risk factor for early initiation of cigarette smoking in children and maternal cigarette smoking appears to be a risk factor for ADHD. Finally, animal studies in rats and monkeys also suggest that nicotine may be involved in attentional systems and locomotor activity. The nicotinic system has previously been studied in schizophrenia where the neuronal nicotinic acetylcholine receptor α7 subunit gene (CHRNA7) has been implicated in decreased P50 inhibition and attentional disturbances in patients with schizophrenia and in many of their nonschizophrenic relatives. Three known microsatellite markers (D15S165, D15S1043, and D15S1360) near the nicotinic acetylcholine α7 receptor gene, CHRNA7, were studied in 206 ADHD parent-proband trios of children aged 5–16 with ADHD according to DSM-IV criteria. Children with known major medical or psychiatric conditions or mental retardation (IQ &lt; 70) were excluded from the study. Markers D15S165 and D15S1360 were in linkage disequilibrium. The extended Transmission Disequilibrium Test analyses demonstrated no evidence that variation at the microsatellite markers D15S1360, D15S1043, and D15S165 influences susceptibility to ADHD. However, it remains possible that the CHRNA7 gene and other nicotinic system genes may be involved in conferring susceptibility to ADHD. © 2001 Wiley-Liss, Inc.

Estrogen and thyroid hormones exert effects on growth, development, and differentiation of the nervous system. Hormone administration can lead to changes in behavior, suggesting that genetic variants of the estrogen receptor α (ERα) and the thyroid hormone receptor α (TRα) genes may predispose to psychiatric diseases. To investigate this possibility, regions of likely functional significance (all coding exons and flanking splice junctions) of the ERα and TRα genes were scanned in patients with schizophrenia (113), along with pilot studies in patients with bipolar illness (BPI), puerperal psychosis, autism, attention-deficit hyperactivity disorder (ADHD), and alcoholism. A total of 1.18 megabases of the ERα gene and 1.16 megabases of the TRα gene were scanned with Detection of Virtually All Mutations-SSCP (DOVAM-S), a method that detects virtually all mutations. Four missense mutations, seven silent mutations and one deletion were identified in the ERα gene, while only four silent mutations were present in the TRα gene. Two of the missense mutations in ERα are conserved in the six available mammalian and bird species (H6Y, K299R) and a third sequence variant (P146Q) is conserved in mammals, birds, and Xenopus laevis, hinting that these sequence changes will be of functional significance. These changes were found in one patient each with BPI, puerperal psychosis, and alcoholism, respectively. Analysis of the ERα and TRα genes in 240 subjects reveals that missense changes and splice site variants are uncommon (1.7% and 0%, respectively). Further analyses are necessary to determine if the missense mutations identified in this study are associated with predisposition or outcome for either psychiatric or nonpsychiatric diseases. © 2001 Wiley-Liss, Inc.

Bipolar disorder is a major psychiatric illness that has evidence for a significant genetic contribution toward its development. In recent years, the BalI RFLP (restriction fragment length polymorphism) in the dopamine D3 receptor gene has been examined as a possible susceptibility factor for both schizophrenia and bipolar disorder. While analysis in schizophrenia has produced examples of increased homozygosity in patients, less encouraging results have been found for bipolar disorder. Recently, however, a family-based association study has found a significant excess of allele 1 and allele 1–containing genotypes in transmitted alleles to bipolar probands over nontransmitted controls. In a large bipolar case control sample (n = 454), we have been unable to replicate the family-based association study (chi-square = 0.137, P = 0.71, 1 df) or detect an effect similar to the positive homozygosity findings in schizophrenia (chi-square = 0.463, P = 0.50, 1 df). A meta-analysis of previous association studies also revealed no difference in allele distributions between bipolar patients and controls for this polymorphism in ethnically homogeneous samples (odds ratio, OR, = 1.04; P = 0.60; 95% confidence interval, CI, = 0.89–1.20). In view of this evidence, we conclude that variation at the BalI RFLP is not an important factor influencing the susceptibility to bipolar disorder. It remains possible, however, that other sequence variations within the DRD3 gene could play a role. © 2001 Wiley-Liss, Inc.

Genetic factors undoubtedly play an important role in determining vulnerability to bipolar disorder but the task of finding susceptibility genes is not trivial. Candidate gene studies, usually employing the association approach, offer the potential to discover the genes of relatively modest effect size that are expected for a complex genetic disorder. Candidate gene approaches depend crucially on our current understanding of disease pathophysiology, and attention has consequently been focussed on a limited range of neurotransmitter systems implicated by the action of drug treatments. Despite no unequivocal, consistently replicated findings, a number of intriguing results have emerged in the literature, both for bipolar disorder in general and for subtypes such as bipolar affective puerperal psychosis and rapid cycling bipolar illness. Genes of particular current interest include those encoding the serotonin transporter, monoamine oxidase A (MAOA) and catechol-O-methyl transferase (COMT). As susceptibility genes are found and knowledge of aetiology advanced it is likely that many more candidate genes in novel biological systems will attract attention.

We have previously reported cosegregation of bipolar affective disorder and Darier disease, a dominant skin disorder with a neuropsychiatric component. The gene for Darier disease was mapped to chromosome 12q23–q24.1 and linkage studies have subsequently implicated this region as harboring a susceptibility gene for bipolar affective disorder. We have genomically characterized the human homologue of murine Cux-2, a neuronal-specific transcription factor potentially involved in the regulation of neural cell adhesion molecule expression that maps to this region. Also, in a panel of 15 unrelated bipolar patients from multiply affected families showing increased allele sharing at markers in the 12q23–q24.1 region, we performed mutational screening of the CUX2 coding sequence, and 5' untranslated region (5' UTR). Resulting sequence were analyzed in a large sample of bipolar patients (n = 218) and control subjects (n = 218). No evidence was found for the involvement of variants within the CUX2 coding, or 5' UTR sequence in producing susceptibility to bipolar disorder. © 2001 Wiley-Liss, Inc.

The glycine receptor, which is a member of the ligandgated ion channel superfamily, mediates synaptic inhibition in the spinal cord and other brain regions. This superfamily has been implicated in the pathogenesis of schizophrenia and other psychiatric diseases. The complete coding sequence and splice junctions of the GLRA2 gene were scanned by DOVAMS, a form of SSCP analysis with sufficient redundancy to detect virtually all mutations. Those analyses were performed in 113 patients with schizophrenia, and in pilot studies of patients with bipolar illness, alcoholism, puerperal psychosis, autism, and attentiondeficit hyperactivity disorder (533 kb total scanned sequences). We detected three sequence changes in the coding region, all resulting in silent mutations C894T in exon 5, C1134T in exon 7, and C1476T in exon 9. These do not alter the structure or the expression of the protein. It is unlikely that mutations in the coding region and splice junction of GLRA2 gene are associated with schizophrenia and other psychiatric diseases.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable, common psychiatric disorder that presents in childhood and that probably involves several genes. There are several lines of evidence suggesting that the nicotinic system may be functionally significant in ADHD (a) nicotine promotes the release of dopamine and has been shown to improve attention in adults with ADHD, smokers and nonsmokers; (b) ADHD is a significant risk factor for early initiation of cigarette smoking in children; (c) maternal cigarette smoking appears to be a risk factor for ADHD; (d) animal studies in rats and monkeys also suggest that nicotine may be involved in attentional systems and locomotor activity; and (e) a central nicotinic agonist, ABT418, improves attention in both monkeys and ADHD adults.

A number of lines of evidence point to the possible involvement of estrogen pathways in the pathophysiology of bipolar disorder in general and puerperal psychosis in particular. There is strong evidence from clinical, follow-up, and genetic studies to support the hypothesis that most cases of puerperal psychosis are manifestations of an affective disorder diathesis with a puerperal trigger and that genes influence susceptibility to both diathesis and trigger. The nature of the trigger is unknown but in view of the abrupt onset at a time of major physiological change it is widely believed that biological, probably hormonal, mechanisms are of paramount importance, with estrogen receiving the most attention to date. We have undertaken a case control association study of bipolar disorder and puerperal psychosis at two known polymorphisms within the estrogen receptor α gene (ESR 1) in a sample of 219 unrelated bipolar probands and 219 controls. We could exclude these polymorphisms from an important contribution to susceptibility to bipolar disorder with a high level of confidence. We found no support for the hypothesis that they contribute specific susceptibility to the puerperal trigger, but due to the small numbers of puerperal probands (n = 26) no firm conclusions can be drawn regarding their involvement in puerperal psychosis. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:850–853, 2000. © 2000 Wiley-Liss, Inc.

The macrophage theory of depression proposes that an excessive secretion of monocyte macrophage cytokines causes symptoms of depression. It has been suggested that changes in immune function that accompany pregnancy and childbirth could contribute to the affective symptoms suffered by many puerperal women. Tumour necrosis factor TNF is a proinflammatory cytokine that has been implicated in inflammatory infections and immune diseases. Production of TNF has been shown to be regulated by oestrogen, which suggests it as a potential candidate for susceptibility to postpartum mood disorders.

Steroid hormone administration causes behavior changes in many and psychosis in a few. The clinical features suggest that genetic variants of the glucocorticoid receptor or cofactors could produce susceptible subpopulations who react adversely to hormonal cascades. To investigate this possibility, coding and splice site sequences of the glucocorticoid receptor were scanned for single nucleotide polymorphisms in genomic DNA samples from 100 schizophrenics (86 Caucasians and 14 African-Americans) and 40 Caucasians with puerperal psychosis. Five amino acid substitutions were found in the amino-terminal domain at frequencies of 0.6 to 3.8% in Caucasians: R23K, F29L, L112F, D233N, and N363S. In addition, four silent nucleotide changes were found: E22E, K293K, D677D, and N766N; a transversion in intron 4 occurred beyond the splice junction. None of these variants can be linked to these disorders at present. However, the N363S variant contributes a new potential phosphorylation site and has been associated with increased body mass and reduced bone mineral density [Huizenga et al., 1998], so it is possible that the other missense variants confer traits that currently are unrecognized. Comparisons to natural glucocorticoid receptor mutants in the familial glucocorticoid resistance syndrome and steroid resistant leukemias suggest that amino acid substitutions at highly conserved residues may cause severe functional defects and serious illness, while changes at less conserved sites produce lesser alterations and milder disease. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:412–417, 2000. © 2000 Wiley-Liss, Inc.